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Q&A: FDA Inspections of Clinical Investigators: Understanding the Process and What to Expect

In a recent webinar, Advarra experts Constance Cullity and Michele Russell-Einhorn presented FDA Inspections of Clinical Investigators: Understanding the Process and What to Expect. Due to time constraints, we were unable to answer all audience questions during the Q&A period, so our experts have responded to additional questions in this blog Q&A.

Q: What is the likelihood an investigator-initiated Investigational New Drug application (IND) and non-IND study would undergo an FDA inspection at an academic center?

A: Investigator-initiated IND and non-IND studies at academic centers and elsewhere can be subject to an FDA audit. FDA may audit non-IND studies involving an FDA-regulated product.

Q: For multisite studies, does FDA inspect all sites, or might one specific site be selected to be monitored?

A: For routine inspections done in support of marketing applications, FDA generally inspects some of the sites in a multisite study but may also inspect all sites if warranted.

Q: Does the inspector directly access clinical site systems, like the electronic medical record (EMR)?

A: FDA may directly access clinical site systems and electronic medical records. How an FDA investigator handles review of EMRs during a clinical investigator (CI) inspection may vary depending on the person and any FDA policies that may affect that person’s permission to use on-site computers.

Q: Does the FDA evaluate systems (such as electronic consents) being part 11 compliant during a site inspection?

A: FDA may evaluate for compliance with relevant aspects of 21 CFR part 11 during a CI inspection.

Q: Is it required to de-identify records with protected health information (PHI) given to the inspector to go off-site?

A: The Health Insurance Portability and Accountability Act (HIPAA) permits covered entities to disclose PHI, without authorization, to public health authorities who are legally authorized to receive the PHI. FDA is authorized, under HIPAA, to receive PHI during FDA Bioresearch Monitoring (BIMO) inspections. FDA may review and copy relevant records that contain PHI, and FDA investigators may take copies of those records with them when they leave the inspection site.

Q: Can a fully executed paper or digital consent form be modified in any way? E.g., noting a file location, fixing a typo, etc.

A: For FDA-regulated clinical trials, FDA regulations are silent on whether minor modifications like those described may be made to a fully executed informed consent form (ICF). However, IRB approval could be needed to make such a change to a fully executed ICF. We suggest posing the question to the IRB of record overseeing any research in which you would want to modify a fully executed ICF.

Q: Are principal investigators (PIs) required to be listed on and delegated tasks in a delegation of authority (DOA) log?

A: DOA logs are not required by FDA regulations and are not discussed in FDA guidance documents for CIs. They are also not on the list of Essential Documents in the International Council for Harmonisation (ICH) Harmonised Guideline E6 (R2): Guideline for Good Clinical Practice. However, a sponsor may impose its own requirements for DOA logs and may require that PIs be listed on them.

Q: What about the role of study monitors in a CI inspection? Can they also participate? How can they support?

A: FDA inspects CIs as individuals. Generally, FDA cannot require third parties to participate in CI inspections. It is generally up to the CI whether to involve any other parties, including a study monitor, in the inspection.

Q: How do you suggest research staff/coordinators educate clinical investigators (CIs) that they need to pay attention to study oversight and the FDA will not hold coordinators responsible by FDA if things go awry in the study conduct?

A: Educational opportunities should be made available by the institution or entity where the investigator is located and/or the research is being conducted. Training requirements should be done on a regular basis and can be an ideal way to reinforce regulatory knowledge and responsibilities.

Q: Do you have any different or additional suggestions for sponsor-investigator inspections?

A: FDA’s sponsor-investigator inspections involve assessing compliance with FDA requirements for both sponsors and CIs. For more information on that type of inspection, please see FDA Compliance Program 7348.811 (Clinical Investigators and Sponsor-Investigators) and FDA Compliance Program 7348.810 (Sponsors, Contract Research Organizations, and Monitors).

Q: Is the establishment inspection report (EIR) only available after the inspection, or is there a draft sites can get at the closeout discussion?

A: The EIR is not prepared until after the inspection ends. Our recommendation during the webinar was meant to suggest requesting a copy of the EIR during the inspection, with the understanding that the EIR would not be available until a later date.

Q: If the FDA has no observations by the end of the inspection, is there any documentation provided confirming this?

A: The lack of a Form FDA 483 (Inspectional Observations) at the close of a CI inspection generally indicates that the FDA investigator did not have any significant observations during the inspection. Documentation confirming there were no significant findings would generally come later, in the form of post-inspectional correspondence from the FDA Center that issued the inspection assignment, if that FDA Center agreed the inspection did not uncover significant findings.

Q: In responding to a 483, does a corrective and preventive action (CAPA) need to be implemented by the CI who was inspected or is there an expectation that an entire facility/institution implement it across their research enterprise (especially when the CAPA is related to a process change)?

A: The FDA inspects CIs as individuals. Therefore, the CI should respond to any issued 483 to that person and should implement appropriate CAPAs to address the inspectional observations. Implementation of a CAPA across a facility or institution could be warranted depending upon the type of concern and issue that needs to be addressed.

Q: Do you anticipate inspections to pick back up as more people become vaccinated and COVID-19 cases decrease? Will the FDA catch up on missed investigations?

A: We anticipate that FDA inspections will probably pick back up once the pandemic subsides, but the extent to which that might occur is not clear. In March 2021, FDA stated, “As we look to the future, the FDA will continue to leverage and maximize every available tool and resource to meet our inspectional responsibilities while achieving optimal public health outcomes…. In concert with these efforts, we are pursuing agency-wide preparedness efforts for resuming a more normal state of operations, which will factor in how best to address inspectional activities that were paused due to the pandemic.”

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